Autoproteolysis of PIDD marks the bifurcation between pro-death caspase-2 and pro-survival NF-κB pathway

Tinel, Antoine; Janssens, Sophie; Lippens, Saskia; Cuenin, Solange; Logette, Emmanuelle; Jaccard, Bastienne; Quadroni, Manfredo; Tschopp, Jürg
January 2007
EMBO Journal;1/10/2007, Vol. 26 Issue 1, p197
Academic Journal
Upon DNA damage, a complex called the PIDDosome is formed and either signals NF-κB activation and thus cell survival or alternatively triggers caspase-2 activation and apoptosis. PIDD (p53-induced protein with a death domain) is constitutively processed giving rise to a 48-kDa N-terminal fragment containing the leucine-rich repeats (LRRs, PIDD-N) and a 51-kDa C-terminal fragment containing the death domain (DD, PIDD-C). The latter undergoes further cleavage resulting in a 37-kDa fragment (PIDD-CC). Here we show that processing occurs at S446 (generating PIDD-C) and S588 (generating PIDD-CC) by an auto-processing mechanism similar to that found in the nuclear pore protein Nup98/96 and inteins. Auto-cleavage of PIDD determines the outcome of the downstream signaling events. Whereas initially formed PIDD-C mediates the activation of NF-κB via the recruitment of RIP1 and NEMO, subsequent formation of PIDD-CC causes caspase-2 activation and thus cell death. A non-cleavable PIDD mutant is unable to translocate from the cytoplasm to the nucleus and loses both activities. In this way, auto-proteolysis of PIDD might participate in the orchestration of the DNA damage-induced life and death signaling pathways.


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